5-arylsulfonyl-imidazo[1&#39;2&#39;:1,6]pyrido[2,3-b]pyrazine-6-amines and related compounds

ABSTRACT

A compound of the formula  
                 
 
     wherein a, X, R 1 , R 2 , R 3  and R 4  are as defined above, useful in the treatment of respiratory, allergic, rheumatoid, body weight regulation, inflammatory and central nervous system disorders such as asthma, chronic obstructive pulmonary disease, adult respiratory diseases syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis, atopic dermatitis, psoriasis, weight control, rheumatoid arthritis, cachexia, crohn&#39;s disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, depression, multi-infarct dementia and AIDS.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This non-provisional patent application is based upon and claimspriority from U.S. patent application Ser. No. 09/489,689, filed Jan.24, 2000, which claims priority from U.S. provisional patent applicationNo. 60/117,875, filed Jan. 29, 1999.

BACKGROUND OF THE INVENTION

[0002] This invention relates to 5-arylsulfonyl-imidazo[1′,2′:1,6]pyrido[2,3-b]pyrazine-6-amines and related compounds. Thecompounds are selective inhibitors of phosphodiesterase type 4 (PDE4)and the production of tumor necrosins factor (TNF), and as such areuseful in the treatment of respiratory, allergic, rheumatoid, bodyweight regulation, inflammatory and central nervous system disorderssuch as asthma, chronic obstructive pulmonary disease, adult respiratorydiseases syndrome, shock, fibrosis, pulmonary hypersensitivity, allergicrhinitis, atopic dermatitis, psoriasis, weight control, rheumatoidarthritis, cachexia, Crohn's disease, ulcerative colitis, arthriticconditions and other inflammatory diseases, depression, multi-infarctdementia, and AIDS.

[0003] This invention also relates to a method of using such compoundsin the treatment of the foregoing diseases in mammals, especiallyhumans, and to pharmaceutical compositions containing such compounds.

[0004] Since the recognition that cyclic adenosine tri-phosphate (cAMP)is an intracellular second messenger, inhibition of thephosphodiesterases has been a target for modulation and, accordingly,therapeutic intervention in a range of disease processes. More recently,distinct classes of PDE have been recognized and their selectiveinhibition has led to improved drug therapy. More particularly, it hasbeen recognized that inhibition of PDE4 can lead to inhibition ofinflammatory mediator release and airway smooth muscle relaxation. Thus,compounds that inhibit PDE4, but which have poor activity against otherPDE types, would inhibit the release of inflammatory mediators and relaxairway smooth muscle without causing cardiovascular effects orantiplatelet effects.

[0005] Recent molecular cloning has revealed a complexity and diversityof PDE4 enzymes. It is now known that there are four distinct PDE4isozymes (A, B, C and D), each encoded for by a separate gene. Kineticstudies of human recombinant materials suggest that these four isozymesmay differ in their Km's and Vmax's for hydrolysis of cAMP. Analysis oftissue distribution of PDE4 mRNAs suggests that each isozyme may belocalized in a cell-specific pattern.

SUMMARY OF THE INVENTION

[0006] The present invention relates to a compound of the formula

[0007] and the pharmaceutically acceptable salts thereof; wherein

[0008] a is 1, 2, 3 or 4;

[0009] X is CH or N;

[0010] R¹ and R² are each independently selected from hydrogen,(C₁-C₆)alkyl, cyano, amino, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino,(C₃-C₇)cycloalkyl, (C₆-C₁₀)aryl and a saturated or unsaturated, cyclicor bicyclic (C₂-C₉)heterocyclic group containing as the heteroatom oneto four of the group consisting of oxygen, sulfur, nitrogen or NR⁶wherein R⁶ is hydrogen or (C₁-C₆)alkyl;

[0011] R³ and R⁴ are each independently selected from hydrogen, halo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano, hydroxy, amino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkoxy,(C₆-C₁₀)aryl or a saturated or unsaturated, cyclic or bicyclic(C₂-C₉)heterocyclic group containing as the heteroatom one to four ofthe group consisting of oxygen, sulfur, nitrogen or NR⁶ wherein R⁶ isdefined as above;

[0012] or R¹ and R² may be taken together with the carbons to which theyare attached to form a compound of formula II

[0013] wherein a, X, R³ and R⁴ are as defined above;

[0014] b is 1, 2, 3 or 4; and

[0015] R⁵ is hydrogen, halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano,hydroxy, amino, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino,(C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkoxy, (C₆-C₁₀)aryl or a saturated orunsaturated, cyclic or bicyclic (C₂-C₉)heterocyclic group containing asthe heteroatom one to four of the group consisting of oxygen, sulfur,nitrogen or NR⁶ wherein R⁶ is defined as above.

[0016] The term “alkyl”, as used herein, unless otherwise indicated,includes saturated monovalent hydrocarbon radicals having straight,branched or cyclic moieties or combinations thereof.

[0017] The term “a saturated or unsaturated, cyclic or bicyclic (C₂-C₉)heterocyclic group containing as the heteroatom one to four of the groupconsisting of oxygen, sulfur, nitrogen or NR⁶ wherein R⁶ is as definedabove”, as used herein, unless otherwise indicated, includes but is notlimited to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl,methylenedioxyl, chromenyl, isoxazolidinyl, 1,3-oxazolidin-3-yl,isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl,1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl,1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl,tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl,1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, chromanyl,furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl,isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl,1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl,1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl,1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl,purinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl,5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl,benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl,isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl,indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl,quinoxalinyl, quinazolinyl and benzoxazinyl.

[0018] The term “halo”, as defined herein, includes fluoro, chloro,bromo or iodo.

[0019] Preferred compounds of formula I include those wherein X isnitrogen.

[0020] Other preferred compounds of formula I include those wherein R¹is hydrogen, (C₁-C₆)alkyl, amino, cycloalkyl or (C₆-C₁₀)aryl.

[0021] Other preferred compounds of formula I include those wherein R²is hydrogen, (C₁-C₆)alkyl, amino, cycloalkyl or (C₆-C₁₀)aryl.

[0022] Other preferred compounds of formula I include those wherein R³is hydrogen, halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano, amino, hydroxy,cycloalkyl or (C₆-C₁₀)aryl.

[0023] Other preferred compounds of formula I include those wherein R⁴is hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, amino, hydroxy, cycloalkyl or(C₆-C₁₀)aryl.

[0024] Other preferred compounds of formula II include those wherein R⁵is hydrogen, halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano, amino, hydroxy,cycloalkyl or (C₆-C₁₀)aryl.

[0025] More preferred compounds of formula I include those wherein X isnitrogen; R¹ is hydrogen, (C₁-C₆)alkyl, amino, cycloalkyl or(C₆-C₁₀)aryl; R² is hydrogen, (C₁-C₆)alkyl, amino, cycloalkyl or(C₆-C₁₀)aryl; R³ is hydrogen, halo, (C₁-C₆)alkyl, cyano, amino, hydroxy,cycloalkyl or (C₆-C₁₀)aryl; and R⁴ is hydrogen, (C₁-C₆)alkyl, amino,hydroxy, cycloalkyl or (C₆-C₁₀)aryl.

[0026] More preferred compounds of formula II include those wherein X isnitrogen; R³ is hydrogen, halo, (C₁-C₆)alkyl, cyano, amino, hydroxy,cycloalkyl or (C₆-C₁₀)aryl; R⁴ is hydrogen, (C₁-C₆)alkyl, amino,hydroxy, cycloalkyl or (C₆-C₁₀)aryl and R⁵ is hydrogen, (C₁-C₆)alkyl,cyano, amino, hydroxy, cycloalkyl or (C₆-C₁₀)aryl.

[0027] Specific preferred compounds of formula I include the following:

[0028]5-[(4-methylphenyl)sulfonyl]-imidazo[1′,2′:1,6]pyrido[2,3-b]pyrazin-6-amine;

[0029]5-[(4-methylphenyl)sulfonyl]-[1,2,4]triazolo[4′,3′:1,6]pyrido[2,3-b]pyrazin-6-amine;

[0030]5-[(4-ethylphenyl)sulfonyl]-imidazo[1′,2′:1,6]pyrido[2,3-b]pyrazin-6-amine;

[0031]5-[(4-isopropylphenyl)sufonyl]-imidazo[1′,2′:1,6]pyrido[2,3-b]pyrazin-6-amine;

[0032]5-[(4-propylphenyl)sulfonyl]-imidazo[1′,2′:1,6]pyrido[2,3-b]pyrazin-6-amine;

[0033]5-[(4-methoxyphenyl)sulfonyl]-imidazo[1′,2′:1,6]pyrido[2,3-b]pyrazin-6-amine;

[0034]5-[(4-ethylphenyl)sulfonyl]-[1,2,4]triazolo[4′,3′:1,6]pyrido[2,3-b]quinoxaline-4-amine;

[0035]5-[(4-fluorophenyl)sulfonyl]-imidazo[1′,2′:1,6]pyrido[2,3-b]pyrazin-6-amine;

[0036]5-[(4-chlorophenyl)sulfonyl]-imidazo[1′,2′:1,6]pyrido[2,3-b]pyrazin-6-amine;

[0037]5-[(3-methoxyphenyl)sulfonyl]-imidazo[1′,2′:1,6]pyrido[2,3-b]pyrazin-6-amine;

[0038]5-[(4-methoxyphenyl)sulfonyl]-[1,2,4]triazolo[4′,3′:1,6]pyrido[2,3-b]pyrazin-6-amine;and

[0039]5-[(4-methoxyphenyl)sulfonyl]-[1,2,4]triazolo[4′,3′:1,6]pyrido[2,3-b]quinoxaline-4-amine;

[0040] The present invention also relates to a pharmaceuticalcomposition for the treatment of respiratory, allergic, rheumatoid, bodyweight regulation, inflammatory and central nervous system disorderssuch as asthma, chronic obstructive pulmonary disease, adult respiratorydiseases syndrome, shock, fibrosis, pulmonary hypersensitivity, allergicrhinitis, atopic dermatitis, psoriasis, weight control, rheumatoidarthritis, cachexia, Crohn's disease, ulcerative colitis, arthriticconditions and other inflammatory diseases, depression, multi-infarctdementia and AIDS in a mammal, including a human, comprising an amountof a compound of the formula I or a pharmaceutically acceptable saltthereof, effective in such treatment and a pharmaceutically acceptablecarrier.

[0041] The present invention also relates to a method for the treatmentof respiratory, allergic, rheumatoid, body weight regulation,inflammatory and central nervous system disorders such as asthma,chronic obstructive pulmonary disease, adult respiratory diseasessyndrome, shock, fibrosis, pulmonary hypersensitivity, allergicrhinitis, atopic dermatitis, psoriasis, weight control, rheumatoidarthritis, cachexia, Crohn's disease, ulcerative colitis, arthriticconditions and other inflammatory diseases, depression, multi-infarctdementia and AIDS in a mammal, including a human, comprisingadministering to said mammal an amount of a compound of the formula I ora pharmaceutically acceptable salt thereof, effective in such treatment.

DETAILED DESCRIPTION OF THE INVENTION

[0042] The following reaction Schemes illustrate the preparation ofcompounds of the present invention. Unless otherwise indicated a, b, X,R¹, R², R³, R⁴ and R⁵ in the reaction Schemes and the discussion thatfollow are defined as above.

[0043] In reaction 1 of Scheme 1, the benzenesulfonyl chloride compoundof formula III is converted to the corresponding cyano compound offormula IV by in situ reduction of III to the corresponding sulfinatesalt followed by reaction with a haloacetonitrile, preferablybromoacetonitrile. The reaction mixture so formed is heated at atemperature between about 50° C. to about 70° C., preferably about 60°C., for a time period between about 1 hour to about 3 hours, preferablyabout 2 hours.

[0044] In reaction 2 of Scheme 1, the compound of formula IV isconverted to the corresponding pyrazineacetonitrile compound of formulaV by reacting IV with a 2,3-dichloropyrazine compound of formula

[0045] in the presence of potassium carbonate and a polar aproticsolvent, such as dimethylformamide. The reaction mixture is heated at atemperature between about 70° C. to about 90° C., preferably about 80°C., for a time period between about 6 hours to about 8 hours, preferablyabout 7 hours.

[0046] In reaction 3 of Scheme 1, the pyrazineacetonitrile compound offormula V is converted to the corresponding5-arylsulfonyl-imidazo[1′,2′:1,6]pyrido[2,3-6]pyrazine-6-amine compoundof formula I by reacting V with a 1-methylimidazole, when X is CH, or a1-methyl-1,2,4-triazole, when X is N, in a polar aprotic solvent, suchas dimethylformamide. The reaction mixture so formed is heated to atemperature of about 140° C. to about 180° C., preferably 160° C., for atime period between about 1 hour to about 8 hours, preferably about 6hours.

[0047] In reaction 1 of Scheme 2, the compound of formula IV isconverted to the corresponding benzopyrazineacetonitrile compound offormula VI by reacting IV with a dichlorobenzopyrazine compound of theformula

[0048] in the presence of potassium carbonate and a polar apoticsolvent, such as dimethylformamide. The reaction mixture is heated at atemperature between about 70° C. to about 90° C., preferably about 80°C., for a time period between about 6 hours to about 8 hours, preferablyabout 7 hours.

[0049] In reaction 2 of Scheme 2, the compound of formula VI isconverted to the corresponding compound of formula II according to theprocedure described above in reaction 3 of Scheme 1.

[0050] The compounds of formula I that are basic in nature are capableof forming a wide variety of different salts with various inorganic andorganic acids. Although such salts must be pharmaceutically acceptablefor administration to humans or animals, it is often desirable inpractice to initially isolate the compound of formula I from thereaction mixture as a pharmaceutically unacceptable salt and then simplyconvert the latter back to the free base compound by treatment with analkaline reagent and subsequently convert the latter free base to apharmaceutically acceptable acid addition salt. The acid addition saltsof the base compounds of this invention are readily prepared by treatingthe base compound with a substantially equivalent amount of the chosenmineral or organic acid in an aqueous solvent medium or in a suitableorganic solvent, such as methanol or ethanol. Upon evaporation of thesolvent, the desired solid salt is readily obtained. The desired acidaddition salt can also be precipitated from a solution of the free basein an organic solvent by adding to the solution an appropriate mineralor organic acid. Pharmaceutically acceptable salts of amino groupsinclude hydrochloride, hydrobromide, sulfate, hydrogen sulfate,phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate,citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) andp-toluenesulfonate (tosylate) salts. Cationic salts of the compounds offormula I are similarly prepared except through reaction of a carboxygroup with an appropriate cationic salt reagent such as sodium,potassium, calcium, magnesium, ammonium, N,N′-dibenzylethylenediamine,N-methylglucamine (meglumine), ethanolamine, tromethamine, ordiethanolamine.

[0051] Those compounds of the present invention that are acidic innature are capable of forming base salts with various pharmacologicallyacceptable cations. Examples of such salts include the alkali metal oralkaline-earth metal salts and particularly, the sodium and potassiumsalts. These salts are all prepared by conventional techniques. Thechemical bases which are used as reagents to prepare thepharmaceutically acceptable base salts of this invention are those whichform non-toxic base salts with the acidic compounds of the presentinvention. Such non-toxic base salts include those derived from suchpharmacologically acceptable cations as sodium, potassium calcium andmagnesium, etc. These salts can easily be prepared by treating thecorresponding acidic compounds with an aqueous solution containing thedesired pharmacologically acceptable cations, and then evaporating theresulting solution to dryness, preferably under reduced pressure.Alternatively, they may also be prepared by mixing lower alkanolicsolutions of the acidic compounds and the desired alkali metal alkoxidetogether, and then evaporating the resulting solution to dryness in thesame manner as before. In either case, stoichiometric quantities ofreagents are preferably employed in order to ensure completeness ofreaction and maximum yields of the desired final product.

[0052] For administration to humans in the curative or prophylactictreatment of inflammatory diseases, oral dosages of a compound offormula I or a pharmaceutically acceptable salt thereof (the activecompounds) are generally in the range of 0.1 to 1000 mg daily, in singleor divided doses, for an average adult patient (70 kg). The activecompounds can be administered in single or divided doses. Individualtablets or capsules should generally contain from 0.1 to 100 mg ofactive compound, in a suitable pharmaceutically acceptable vehicle orcarrier. Dosages for intravenous administration are typically within therange of 0.1 to 10 mg per single dose as required. For intranasal orinhaler administration, the dosage is generally formulated as a 0.1 to1% (w/v) solution. In practice the physician will determine the actualdosage which will be most suitable for an individual patient and it willvary with the age, weight and response of the particular patient. Theabove dosages are exemplary of the average case but there can, ofcourse, be individual instances where higher or lower dosage ranges aremerited, and all such dosages are within the scope of this invention.

[0053] For human use, the active compounds of the present invention canbe administered alone, but will generally be administered in anadmixture with a pharmaceutical diluent or carrier selected with regardto the intended route of administration and standard pharmaceuticalpractice. For example, they may be administered orally in the form oftablets containing such excipients as starch or lactose, or in capsuleseither alone or in admixture with excipients, or in the form of elixirsor suspensions containing flavoring or coloring agents. They may beinjected parenterally; for example, intravenously, intramuscularly orsubcutaneously. For parenteral administration, they are best used in theform of a sterile aqueous solution which may contain other substances;for example, enough salts or glucose to make the solution isotonic.

[0054] Additionally, the active compounds may be administered topicallywhen treating inflammatory conditions of the skin and this may be doneby way of creams, jellies, gels, pastes, and ointments, in accordancewith standard pharmaceutical practice.

[0055] The therapeutic compounds may also be administered to a mammalother than a human. The dosage to be administered to a mammal willdepend on the animal species and the disease or disorder being treated.The therapeutic compounds may be administered to animals in the form ofa capsule, bolus, tablet or liquid drench. The therapeutic compounds mayalso be administered to animals by injection or as an implant. Suchformulations are prepared in a conventional manner in accordance withstandard veterinary practice. As an alternative the therapeuticcompounds may be administered with the animal feedstuff and for thispurpose a concentrated feed additive or premix may be prepared formixing with the normal animal feed.

[0056] The ability of the compounds of formula I or the pharmaceuticallyacceptable salts thereof to inhibit PDE₄ may be determined by thefollowing assay.

Inhibition of PDE4 Isozymes

[0057] Preparation of test compounds:

[0058] Compounds are dissolved in dimethyl sulfoxide at a concentrationof 1×10⁻² M, or to a desired higher concentration if solubility is anissue then diluted 1:25 in water (4×10⁻⁴ M compound, 4% DMSO). Furtherserial dilutions are made in 4% dimethyl sulfoxide to achieve desiredconcentrations. Final dimethyl sulfoxide concentration in assay is 1%.

[0059] In duplicate, the following are added in order to a scintillationvial (all concentrations are given as final concentrations in vial).

[0060] 25 μl compound of dimethyl sulfoxide (1%, for blank)

[0061] 25 μl [³H] cAMP-containing assay buffer (1 μM [³H] cAMP, 50 mMTris, 10 mM MgCl₂, pH 7.5)

[0062] 25 μl 5′-nucleotidase (0.001 unit) (Sigma #N5880)

[0063] 25 μl PDE4 isozyme (1/1200-1/2400 dilution in Prep #1)

[0064] The reaction vials are shaken and placed in a water bath (3.7°C.) for 30 minutes, at which time the reaction is stopped by adding 1 mlDowex 1×8 resin, chloride form (1:3 slurry in distilled water). Three mlReady Safte scintillation fluid are added directly to each vial. Mixeach vial well and count radioactivity after resin has settled (approx.4 hours at room temperature).

[0065] Data Calculation and Interpretation

[0066] Percent inhibition is determined by the formula:${\% \quad {inh}} = {1 - {\frac{{{{avg}.\quad {cpm}}\quad \left( {{test}\quad {compound}} \right)} - {{{avg}.\quad {cpm}}\quad ({blank})}}{{{avg}.\quad {cpm}}\quad \left( {{{control}\left( {{no}\quad {compound}} \right)} - {{{avg}.\quad {cpm}}\quad ({blank})}} \right.} \times 100}}$

[0067] IC50 is defined as that concentration of compound which inhibits50% of radioactivity, and is determined by Microsoft Excel or otherappropriate software.

[0068] The present invention is illustrated by the following examples,but is not limited to the details thereof.

Preparation 1 [(4-Ethylphenyl)sulfonyl]-acetonitrile

[0069] In a 125 mL, three-necked flask fitted with thermometer, additionfunnel, and glass stopper was placed 11.5 grams (91.2 mmol) of sodiumsulfite, 8.32 grams (97.7 mmol) of sodium bicarbonate, and 50 mL ofwater. After heating the mixture to 75-80° C., 10.0 grams (48.9 mmol) of4-ethylbenzenesulfonyl chloride was added dropwise over 0.5 hours. Whenthe addition was complete, heating was continued for 3 hours at whichtime a white precipitate formed. The suspension was cooled to roomtemperature and allowed to stir for 16 hours. The precipitate wascollected by filtration, washed with cold water, combined with a secondcrop from the filtrate, and dried under high vaccum to give 13.9 grams(>100% yield) of crude sodium 4-ethylbenzenesulfinate.

[0070] In a small Parr bottle was placed the salt above, 3.09 mL (5.33grams, 44.9 mmol) of bromoacetonitrile, and 0.488 grams of aliquat™-336.The contents were agitated on a Vortex-2 Genie™ for 5 minutes using aspatula to maintain homogeneity. The bottle was transferred to an oilbath and heated for 2 hours at 60° C., as the mixture softened, turnedpink-orange, and then hardened. The solid was extracted with 250 mL ofethyl acetate, filtered, and evaporated to a solid. Trituration inmethylene chloride gave 5.61 grams (55% yield) of the title compound asan off-white solid. Melting Point: 120-121° C. Anal. Calcd forC₁₀H₁₁NO₂S: C, 54.40; H, 5.30; N, 6.69. Found: C, 57.29; H, 5.39; N,6.6.1.

Preparations 2-4

[0071] The compounds of Preparations 2-4 were prepared according to theprocedure of Preparation 1 substituting the indicated sulfonyl chloridefor 4-ethylbenzenesulfonyl chloride.

Pre- paration R³ M.P. (° C.) C, H, N Analysis 2 CH(CH₃)₂ 64-66 Calcd forC₁₁H₁₃NO₂S: C, 59.17; H, 5.87; N, 6.27. Found: C, 59.31; H, 5.82; N,6.27. 3 n-C₃H₇ 123-134 Calcd for C₁₁H₁₃NO₂S: C, 59.17; H, 5.87; N, 6.27.Found: C, 59.42; H, 5.82; N, 6.23. 4 OCH₃ 115-117 Calcd for C₉H₉NO₃S: C,51.12; H, 4.29; N, 6.63. Found: C, 51.27; H, 4.16; N, 6.63.

Preparation 53-Chloro-→-[(4-methylphenyl)sulfonyl]-2-pyrazineacetonitrile

[0072] A mixture of 6.38 grams (32.7 mmol) of(4-methylbenzenesulfonyl)acetonitrile (for preparation, see: Bram, G. etal., Synthesis, 1987, 56), 4.87 grams (32.7 mmol) of2,3-dichloropyrazine, 4.97 grams (36.0 mmol) of potassium carbonate, and10 mL of dimethylformamide was heated for 7 hours at 80° C. The solventwas removed by vaccum distillation, and the residue was diluted with 100mL of aqueous 1 N hydrochloric acid solution and extracted with ethylacetate (1×150 mL, 1×100 mL). The combined extracts were washed withbrine (1×100 mL), dried (magnesium sulfate) and evaporated to give 8.9grams of a dark oil. Purification by flash chromatography using a 30-50%ethyl acetate-hexane eluant gave 2.35 grams of solid which wastriturated in ether to afford 2.20 grams (20% yield) of the titlecompound as a white solid. Melting Point: 148-151° C. (lit. 126° C.(Litvinenko, S. V. et al., Chem. Heterocycl. Compd. (Eng. Transl.),1992, 28, 93)). Anal. Calcd for C₁₃H₁₀N₃O₂ClS: C, 50.74; H, 3.28; N,13.65. Found: C, 50.45; H, 3.53; N, 13.77.

Preparations 6-9

[0073] The compounds of Preparations 6-9 were prepared according to theprocedure of Preparation 5 substituting the indicated substrate for(4-methylbenzenesulfonyl)acetonitrile.

Pre- paration R³ Substrate M.P. (° C.) C, H, N Analysis 6 C₂H₅ Compound129-131 Calcd for C₁₄H₁₂N₃O₂ClS: C, 52.26; H, of Pep. 1 3.76; N, 13.06.Found: C, 52.38; H, 3.59; N, 12.97. 7 CH(CH₃)₂ Compound 88-94 Calcd forC₁₅H₁₄N₃O₂ClS: C, 53.49; H, of Prep. 2 4.49; N, 12.48. Found: C, 53.72;H, 4.21; N, 12.47. 8 n-C₃H₇ Compound 100-103 Calcd for C₁₅H₁₄N₃O₂ClS: C,53.49; H, of Prep. 3 4.49; N, 12.48. Found: C, 53.70; H, 4.31; N, 12.34.9 OCH₃ Compound 135-136 Calcd for C₁₃H₁₀N₃O₂ClS: C, 48.23; H, of Prep. 43.11; N, 12.98. Found: C, 48.42; H, 3.15; N, 12.86.

Preparation 103-Chloro-→-[(4-ethylphenyl)sulfonyl]-2-quinoxalineacetonitrile

[0074] The title compound was prepared as a tan powder, melting point208-211° C., according to the procedure of Preparation 5 substitutingthe compound of Preparation 1 for (4-methylbenesulfonyl)acetonitrile andsubstituting 2,3-dichlorquinazoline for 2,3-dichloropyrazine. Calcd forC₁₈H₁₄N₃O₂SCl: C, 58.14 H, 3.79; N, 11.30. Found: C, 58.15; H, 3.59; N,11.32.

EXAMPLE 15-[(4-Methylphenyl)sulfonyl]-imidazo[1′,2′:1,6]pyrido[2,3-b]pyrazin-6-amine

[0075] A mixture of 360 mg (1.17 mmol) of the compound of Preparation 5,0.280 mL (288 mg, 3.51 mmol) of 1-methylimidiazole, and 2 mL ofdimethylformamide was heated for 1.5 hours at 160° C. An additional0.280 mL of 1-methylimidazole was added and heating was continued for4.5 hours. The solvent and excess 1-methylimidazole was removed bydistillation under high vaccum, and the dark solid residue was extractedwith 150 mL of boiling toluene and filtered. The filtrate was evaporatedto give 234 mg of a dark solid brown solid. The insoluble material fromthe hot toluene extract was extracted with 100 mL of boiling chloroform,filtered, and evaporated to give 214 mg of a dark brown solid. Bothsolids were purified separately by flash chromatography using 5%acetone-chloroform as eluant, and the enriched fractions from eachpurification were combined and evaporated to give 301 mg of a yellowsolid. Trituration in ether followed by rercrystallization from tolueneafforded 148 mg (37% yield) of the title compound as a fluffy yellowsolid. Melting Point: 294-295° C. Anal. Calcd for C₁₆H₁₃N₅O₂S: C, 56.63;H, 3.86; N, 20.64. Found: C, 56.87; H, 3.79; N, 20.61.

EXAMPLES 2-6

[0076] The compounds of Examples 2-6 were prepared according to theprocedure of Example 1 substituting the indicated substrate for thecompound of Preparation 5 and, in the case of Example 2, substituting1-methyl-1,2,4-triazole for 1-methylimidazole. In some cases, reactionswere performed neat in excess 1-methylimidazole or1-methyl-1,2,4-triazole.

Example R³ X Substrate M.P. (° C.) Spectral or Analytical Data 2 CH₃ NCompound >300° C. Anal. Calcd for C₁₅H₁₂N₆O₂S: C, 52.93; of Prep. 5 H,3.55; N, 24.69. Found: C, 53.31; H, 3.55; N, 24.68. 3 CH₂CH₃ CH Compound267.5- Anal. Calcd for C₁₇H₁₅N₅O₂S: C, 57.78; of Prep. 6 268.5 H, 4.28;N, 19.82. Found: C, 57.88; H, 4.24; N, 19.77. 4 CH(CH₃)₂ CH Compound241-244 Anal. Calcd for C₁₈H₁₇N₅O₂S: C, 58.84; of Prep. 7 H, 4.66; N,19.06. Found: C, 58.63; H, 4.55; N, 18.88. 5 n-C₃H₇ CH Compound 231-232¹H NMR (DMSO-d⁸) d 0.84 (3H, t, J=7 of Prep. 8 Hz), 1.49-1.61 (2H, m),2.58 (2H, t, J= 7.5Hz), 7.35 (2H, d, J=8Hz), 7.74 (1 H, d, J=1Hz), 7.99(2H, d, J=8Hz), 8.05 (1H, br s), 8.26 (1H, br s), 8.34 (1 H, d,J=2.5Hz), 8.54 (1H, d, J=1Hz), 8.57 (1H, d, J=2.5Hz). 6 OCH₃ CH Compound269-270 ¹HNMR (DMSO-d⁸) d 3.77 (3H, s), 7.01 of Prep. 9 (2H, d, J=8Hz),7.71-7.72 (1H, m), 7.98 (1H, br s), 8.00 (2H, d, J=8Hz), 8.21 (1H, brs), 8.32-8.33 (1H, m), 8.51-8.52 (1H, m), 8.555-8.563 (1 H, m).

EXAMPLE 75-[(4-Ethylphenyl)sulfonyl]-[1,2,4]triazolo[4′,3′:1,6]pyrido[2,3-b]quinoxalin-4-amine

[0077] The title compound was prepared as a fluffy yellow solid, meltingpoint >300° C., according to the procedure Example 1 substituting thecompound of Preparation 10 for the compound of Preparation 5 andsubstituting 1-methyl-1,2,4-triazole for 1-methylimidazole. Calcd forC₁₅H₁₆N₆O₂S: C, 59.39; H, 3.99; N, 20.78. Found: C, 59.33; H, 3.99; N,21.10.

EXAMPLE 85-[(4-Hydroxyphenyl)sulfonyl]-imidazo[1′,2′:1,6]pyrido[2,3-b]pyrazin-6-amine

[0078] A mixture of 97 mg (0.27 mmol) of the compound of Example 6, 360mg (2.7 mmol) of lithium iodide, and 5 mL of collidine was heated for 4hours at 210° C. The solvent was removed by distillation under vaccum,and the residue was taken up in 100 mL of ethyl acetate, washed withsaturated aqueous sodium sulfate solution (1×25 mL), aqueous 1 Nhydrochloric acid solution (1×100 mL), water (1×100 mL), saturatedaqueous sodium sulfate solution (1×50 mL), and brine (1×50 mL). Solidswere removed by filtration, and the filtrate was dried (magnesiumsulfate) and evaporated to give 110 mg of a solid which was trituratedin hot methanol to afford 90 mg (95% yield) of the title compound as abright yellow solid. Melting Point: >300° C. AMPI MS (m/e) 341 (M⁺).

1. A compound of the formula

or a pharmaceutically acceptable salts thereof; wherein a is 1, 2, 3 or4; X is CH or N; R¹ and R² are each independently selected fromhydrogen, (C₁-C₆)alkyl, cyano, amino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, (C₃-C₇)cycloalkyl, (C₆-C₁₀)aryl and a saturated orunsaturated, cyclic or bicyclic (C₂-C₉)heterocyclic group containing asthe heteroatom one to four of the group consisting of oxygen, sulfur,nitrogen or NR⁶ wherein R⁶ is hydrogen or (C₁-C₆)alkyl; R³ and R⁴ areeach independently selected from hydrogen, halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, cyano, hydroxy, amino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkoxy,(C₆-C₁₀)aryl or a saturated or unsaturated, cyclic or bicyclic(C₂-C₉)heterocyclic group containing as the heteroatom one to four ofthe group consisting of oxygen, sulfur, nitrogen or NR⁶ wherein R⁶ isdefined as above; or R¹ and R² may be taken together with the carbons towhich they are attached to form a compound of formula II

wherein a, X, R³ and R⁴ are as defined above; b is 1, 2, 3 or 4; and R⁵is hydrogen, halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano, hydroxy, amino,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkoxy, (C₆-C₁₀)aryl or a saturated or unsaturated, cyclicor bicyclic (C₂-C₉)heterocyclic group containing as the heteroatom oneto four of the group consisting of oxygen, sulfur, nitrogen or NR⁶wherein R⁶ is defined as above.
 2. A compound according to claim 1,wherein X is nitrogen.
 3. A compound according to claim 1, wherein R¹ ishydrogen, (C₁-C₆)alkyl, amino, cycloalkyl or (C₆-C₁₀)aryl.
 4. A compoundaccording to claim 1, wherein R² is hydrogen, (C₁-C₆)alkyl, amino,cycloalkyl or (C₆-C₁₀)aryl.
 5. A compound according to claim 1, whereinR³ is hydrogen, halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano, amino,hydroxy, cycloalkyl or (C₆-C₁₀)aryl.
 6. A compound according to claim 1,wherein R⁴ is hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, amino, hydroxy,cycloalkyl or (C₆-C₁₀)aryl.
 7. A compound according to claim 1, whereinR⁵ is hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano, amino, hydroxy,cycloalkyl or (C₆-C₁₀)aryl.
 8. A compound according to claim 1, whereinX is nitrogen; R¹ is hydrogen, (C₁-C₆)alkyl, amino, cycloalkyl or(C₆-C₁₀)aryl; R² is hydrogen, (C₁-C₆)alkyl, amino, cycloalkyl or(C₆-C₁₀)aryl; R³ is hydrogen, halo, (C₁-C₆)alkyl, cyano, amino, hydroxy,cycloalkyl or (C₆-C₁₀)aryl; and R⁴ is hydrogen, (C₁-C₆)alkyl, amino,hydroxy, cycloalkyl or (C₆-C₁₀)aryl.
 9. A compound according to claim 1,wherein X is nitrogen; R³ is hydrogen, halo, (C₁-C₆)alkyl, cyano, amino,hydroxy, cycloalkyl or (C₆-C₁₀)aryl; R⁴ is hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, amino, hydroxy, cycloalkyl or (C₆-C₁₀)aryl and R⁵ ishydrogen, (C₁-C₆)alkyl, cyano, amino, hydroxy, cycloalkyl or(C₆-C₁₀)aryl.
 10. A compound according to claim 1, wherein said compoundis selected from the group consisting of:5-[(4-methylphenyl)sulfonyl]-imidazo[1′,2′:1,6]pyrido[2,3-b]pyrazin-6-amine;5-[(4-methylphenyl)sulfonyl]-[1,2,4]triazolo[4′,3′:1,6]pyrido[2,3-b]pyrazin-6-amine;5-[(4-ethylphenyl)sulfonyl]-imidazo[1′,2′:1,6]pyrido[2,3-b]pyrazin-6-amine;5-[(4-isopropylphenyl)sufonyl]-imidazo[1′,2′:1,6]pyrido[2,3-b]pyrazin-6-amine;5-[(4-propylphenyl)sulfonyl]-imidazo[1′,2′:1,6]pyrido[2,3-b]pyrazin-6-amine;5-[(4-methoxyphenyl)sulfonyl]-imidazo[1′,2′:1,6]pyrido[2,3-b]pyrazin-6-amine;5-[(4-ethylphenyl)sulfonyl]-[1,2,4]triazolo[4′,3′:1,6]pyrido[2,3-b]quinoxaline-4-amine;5-[(4-fluorophenyl)sulfonyl]-imidazo[1′,2′:1,6]pyrido[2,3-b]pyrazin-6-amine;5-[(4-chlorophenyl)sulfonyl]-imidazo[1′,2′:1,6]pyrido[2,3-b]pyrazin-6-amine;5-[(3-methoxyphenyl)sulfonyl]-imidazo[1′,2′:1,6]pyrido[2,3-b]pyrazin-6-amine;5-[(4-methoxyphenyl)sulfonyl]-[1,2,4]triazolo[4′,3′:1,6]pyrido[2,3-b]pyrazin-6-amine;and5-[(4-methoxyphenyl)sulfonyl]-[1,2,4]triazolo[4′,3′:1,6]pyrido[2,3-b]quinoxaline-4-amine.11. A pharmaceutical composition for the treatment of respiratory,allergic, rheumatoid, body weight regulation, inflammatory and centralnervous system disorders such as asthma, chronic obstructive pulmonarydisease, adult respiratory diseases syndrome, shock, fibrosis, pulmonaryhypersensitivity, allergic rhinitis, atopic dermatitis, psoriasis,weight control, rheumatoid arthritis, cachexia, Crohn's disease,ulcerative colitis, arthritic conditions and other inflammatorydiseases, depression, multi-infarct dementia and AIDS in a mammal,including a human, comprising an amount of a compound of claim 1 or apharmaceutically acceptable salt thereof, effective in such preventionsor treatment and a pharmaceutically acceptable carrier.
 12. A method forthe treatment of respiratory, allergic, rheumatoid, body weightregulation, inflammatory and central nervous system disorders such asasthma, chronic obstructive pulmonary disease, adult respiratorydiseases syndrome, shock, fibrosis, pulmonary hypersensitivity, allergicrhinitis, atopic dermatitis, psoriasis, weight control, rheumatoidarthritis, cachexia, Crohn's disease, ulcerative colitis, arthriticconditions and other inflammatory diseases, depression, multi-infarctdementia and AIDS in a mammal, including a human, comprisingadministering to said mammal an amount of a compound of claim 1 or apharmaceutically acceptable salt thereof, effective in such treatment.